Among pathogens considered likely agents of biological warfare and terrorism (BWT), RNA viruses comprise many of the most amenable for use as weapons. With modest cell culture capacity, large amounts of these viruses can be produced and lyophilized to generate stockpiles of aerosol-infectious material. Many of these viruses are readily available from natural sources, increasing the risk of acquisition by terrorists or governments seeking biological weapons of mass destruction. For these and other reasons, the viruses we propose to study are Category A-C agents, and most are also categorized as select agents by the CDC. Current defense against most BWT RNA viruses is ineffective or non-existent. Ribavirin and interferon are effective against a few BWT RNA viruses but only if administered early during the course of disease, usually before severe disease is apparent; no effective therapy exists for later stages of infection when severe signs such as hemorrhage and encephalitis are first recognized. No licensed vaccines are available for any of the RNA viruses likely to be deployed for biological terrorism or warfare. Furthermore, diagnostic methods for detecting and characterizing human infection can be slow and imprecise. We therefore propose to exploit recent advances in RNA virus genetics, as well as the unique virology expertise within our regional group, to develop 1) cross-cutting, low containment, rapid and high-throughput screening methods for identifying new antiviral drugs against BWT agents; and 2) rapid, sensitive and specific detection systems for identifying infectious BWT viruses and antibodies in infected persons. This research will meet critical, immediate needs for viral biodefense by accelerating the development of antivirals, diagnostics and vaccine development and by moving much of this viral BWT research into the low-containment (BSL-2) arena. Our project will also provide important new tools for basic research on BWT viruses, such as the identification of cellular receptors and mechanisms of pathogenesis, which will benefit both basic and applied virology research now and in the future.